PESTICIDE RESIDUES IN FOOD - 1982
Sponsored jointly by FAO and WHO
EVALUATIONS 1982
Data and recommendations of the joint meeting
of the FAO Panel of Experts on Pesticide Residues
in Food and the Environment and the
WHO Expert Group on Pesticide Residues
Rome, 23 November - 2 December 1982
Food and Agriculture Organization of the United Nations
Rome 1983
METHAMIDOPHOS
CH3O O
\ "
P - NH2
/
CH3S
Explanation
Methamidophos was evaluated for an ADI by the Joint FAO/WHO
Meeting in 1976.1 An ADI was allocated based on a no-effect level
observed in a 90-day dog study not carried out by Industrial Bio-Test
Laboratories (IBT).
Some relevant toxicological studies supporting the 1976
Evaluation of Methamidophos were carried out by IBT, namely,
antidotes, mutagenicity, neurotoxicity, reproduction, teratology,
short-term (rat, dog), long-term (rat) and observations in humans.
The 1982 JMPR was requested to determine the validity of the
various IBT studies. Some substitutive studies have been made
available and are summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Fish
Bluegill (Lepomis macrochirus) were continuously exposed to
14C-methamidophos for a 30-day period at concentrations of 10 and 100
ppb and were held an additional 30 days in fresh, untreated
water. Throughout the 30 days of exposure, the concentration of
14C-methamidophos in the water was in the range of 8 to 10 ppb and 74
to 119 ppb for the expected levels of 10 and 100 ppb, respectively.
14C residues in fish reached a maximum level of 63 and 1 120 ppb in
bluegill exposed to 10 and 100 ppb concentrations, respectively. The
accumulation factors of 8 and 13 ca. were reached in 3 to 7 days and
were maintained for 30 days. The non-edible portion (head, viscera and
scales) contained 44% and 97% of 14C-residues from 10 and 100 ppb
levels, with 99% of the residues extracted into the polar solvent
acetonitrile.
1 See Annex 2 for WHO and FAO documentation
The rate of elimination of accumulated 14C-residues was slow,
and approximately 51 and 39% of the residues from the 10 and 100 ppb
aquaria, respectively, were dissipated in 30 days of withdrawal (Lamb
et al 1980c).
Metabolism
Female houseflies (N-AIDM susceptible strain, and dimethoate-
resistant strain) were treated topically with 32p-methamidophos at
doses of 10, 24 or 48 ng/fly.
32p residues were determined in the holding container rinse, fly
external rinse, fly internal extract and fly unextractable residue.
The data for both external rinses and total penetration show that
absorption was greater and faster in the susceptible NAIDM strain than
in the dimethoate resistant strain, thus, at least in part, explaining
the small but higher cross-resistance of the latter to methamidophos.
Only the parent compound was detected in the holding container,
external fly rinses and internal fly extracts. Fly head ChE bioassay
of the radioactivity quantitated fractions showed no greater
inhibition than would have been produced by similar amounts of
methamidophos. Thus, no direct evidence for the in vivo conversion of
methamidophos to either activation or degradation products was
demonstrable.
The results of incubating methamidophos with cockroach gut or
mouse liver slices, followed by bioassay utilizing housefly head ChE
inhibition, showed that inhibition after incubation essentially
paralleled that of the methamidophos standard. This suggests that
methamidophos did not undergo any major activation or degradative
changes in these systems. When the in vitro incubation extracts were
analysed by paper-chromatography, and the various chromatographic
spots were bioassayed for anticholinesterase activity, only those
spots corresponding to methamidophos were active, and thus the other
spots represent breakdown rather than activation products.
The affinity of methamidophos for ChE and its phosphorylation and
bimolecular inhibition rates are all relatively slow. In treated
flies, knockdown and mortality were first evident nearly 8 hours after
treatment at the LD25 and LD50 levels, but occurred earlier at 4
hours at the LD90 level. The onset and severity of symptoms, and the
degree of ChE inhibition in survivors, were relatively dependent on
the dosage level. With methamidophos, both knockdown and inactivation
of ChE are slow (compared to other effective organophosphorus
insecticides), requiring about 4 to 8 hours for maximum effect. This
appears to be a reflection of the kinetics of its enzyme inhibition,
although the rate of penetration and accumulation in critical
concentrations at the site of activation may also be involved. Its
relative stability and low in vivo degradation appear to be of
critical importance in accumulating and maintaining a sufficient
internal concentration for a sufficiently long period of time to
permit the development of slowly expressed toxicity toward flies
(Khasawinah et al 1978).
In another study, the metabolism of O,S-dimethyl-, propionyl-,
and hexanoyl-phosphoramidothioate was investigated in the Swiss white
mouse and housefly. Compared to the hexanoyl-phosphoramidothioate, the
propionyl analogue is approximately 35-fold more toxic to houseflies
and is 10-fold less toxic to mice. On a percentage basis,
substantially larger amounts of methamidophos were detected in
houseflies treated topically with the propionyl-phosphoramidothioate
than in flies treated with the hexanoyl derivative. The reverse was
evident in the case of the mouse, where much larger amounts of
methamidophos were formed after oral treatment with hexanoyl-
phosphoramidothioate. Minor amounts of other metabolic products
also were detected, including an unknown from hexanoyl-
phosphoramidothioate. Metabolism of the O,S-methyl moiety to carbon
dioxide appeared to be a major pathway for metabolic degradation of
both compounds in both the white mouse and housefly. The difference in
toxicity of the two acyl phosphoramidothioates to the mouse and
housefly is attributed to the differences in the amounts of
methamidophos formed in the animals (Kao and Fukuto 1977).
Effects on Enzymes and other Biochemical Parameters
In vitro determination of cholinesterase (ChE) inhibition showed
that methamidophos is a moderate ChE inhibitor in comparison to other
organophosphates of comparable toxicity. Further, it shows essentially
no selectivity among the three sources of enzyme considered, i.e.
housefly head, honey bee worker head and white mouse brain (I50 (M)
1.1 3.5, 8.2 × 10-5, respectively). Paralleling its
anticholinesterase activity, methamidophos is only a moderate
inhibitor of housefly and bee abdomen aliesterase (AliE).
The results of the in vivo inhibition studies of ChE and AliE in
surviving flies treated topically with methamidophos at the LD25,
LD50 and LD90 levels showed that knockdown and mortality were first
evident nearly 8 hours after treatment at the LD25 and LD50 levels,
but occurred earlier - at 4 hours - at the LD90 level. ChE activities
at these times were drastically reduced in knocked-down and and dead
flies to below 10% of normal activity in heads and to essentially 0%
in thoraxes. In surviving flies, ChE inhibition was slowly progressive
and reached its maximum with the appearance of knockdown effects when
head ChE activities at the LD25, LD50 and LD90 levels were,
respectively, 64, 16 and 16% of normal, and thoracic ChE activities
were, respectively, 56, 12 and 2%. AliE inhibition at LD50 level
after treatment with methamidophos occurs sooner and is more complete
in surviving flies than ChE inhibition, reaching essentially 0% of
normal in 15 hours. AliE and ChE did not recover over a period of
16 hours in the surviving flies. Since essentially total AliE
inhibition occurred much earlier than the appearance of symptoms of
poisoning, its inhibition by methamidophos appears to have little
significance relative to poisoning effects toward flies. Although
inhibition of AliE is not directly related to the toxicity, it may
play an important role in toxicological interactions, such as the
potentiation of toxicity of malathion (Khasawinah et al 1978).
Reactivation of acetylcholinesterase (AChE) inhibited by
MeO(NH2)P(O)SMe (methamidophos) and by MeS(NH2)P (O) SMe was studied
at pH 7.5 and 25°C. The former inhibited enzyme shows a rather rapid
spontaneous reactivation (t1/2=3.7 h); this reactivation is
accelerated by 1 µM of the bispyridinium oximes TMB4 and obidoxime,
and, to a lesser extent, by the monopyridinium oximes P2S and its
1-benzyl analogue (benzyl-P2A). The latter inhibited enzyme shows
rapid ageing (t1/2 = 0.6 h). Reactivation with 1 mM of the
bispyridinium oximes is incomplete and reactivation with 1 mM of the
mono pyridinium oximes proceeds very slowly. These large differences
between the properties of the two inhibited enzymes indicate that the
methylthio group is the leaving group during inhibition of Ache by
methamidophos. Additional support is afforded by the observation of
induced ageing of the former inhibited enzyme by thiourea.
On comparison of the reactivation of AChE inhibited by
methamidophos with that of AChE inhibited by an N-methyl analogue,
crufomate, and an N,N-dimethyl analogue,tabun, it appears that the
rate of spontaneous reactivation decreases with increasing alkylation
of the P-NH2 group. Whereas benzyl-P2A is somewhat less active than
P2S for reactivation of AChE inhibited by methamidophos, it is
superior to P2S for reactivation of AChE inhibited by crufomate and
also superior to P2S and to the bispyridinium oximes for AChE
inhibited by tabun (de Jong et al 1982).
TOXICOLOGICAL STUDIES
Special Studies on Embryotoxicity and Teratogenicity
Groups of rabbits (15 pregnant Himalayan rabbits/group) were
administered single daily doses of methamidophos (62% purity) by oral
intubation equivalent to 0, 0.1, 0.5, 2.5 mg/kg bw from gestation day
6 through 18 (a total of 13 times). Himalaysan rabbits are reported
sensitive to the toxic effect of thalidomide on their embryos/
foetuses. The highest dose (2.5 mg/kg/day) was selected because an
oral dose of 5 mg/kg/day administered 13 times in a preliminary
experiment on 3 female rabbits had produced a weight loss and caused
diarrhoea in one of them. On gestation day 29, the dams were
sacrificed and foetuses were removed by caesarean section for
external, viscera] and skeletal examination. Neither adverse effects
on appearance and behaviour, nor treatment-related mortality were seen
in any of the treated animals. Average weight increase of animals of
all treated groups was clearly lower than control animals (even though
not strictly dose-related) over both the dosing and the entire
gestation period. Since the litter size and foetus weights were
comparable in all groups, the reduced body weight gain of dams was
considered a maternally toxic effect of the treatment. There were no
significant differences between control and treated groups with
respect to fertility rate, pregnancy rate, sex distribution of
foetuses and average numbers of implantations, dead and live foetuses,
resorptions (which includes the number of aborted foetuses), foetus
weight, placentaweight and stunted foetuses (weighing less than
25 grams). Skeletal retardations were found only in the control group
(sternum) and one in the 2.5 mg/kg/day group (os pubis). Some
malformations occurred in all treated groups but not in the control.
However malformations found in treated animals were neither uniform in
type nor dose-related, and both frequency of malformed foetuses and
type of malformations were within the normal limits for this strain of
rabbit. On the basis of the data, there are no indications of
methamidophos having embryotoxic or teratogenic effects on Himalayan
rabbits at oral doses up to and including 2.5 mg/kg/day (Machemer
1979).
Special Studies on Mutagenicity
Mouse - dominant lethal test
Groups of mice (50 male, NMRI/ORIG Kissleg strain/group) were
administered by intubation a single oral dose of 0 and 5 mg/kg bw of
methamidophos (62.6% purity). The mouse strain used for the study is
reported to display a sensitive response to known chemical mutagens,
e.g. cyclophosphamide, MMS or trenimon. The dose of methamidophos was
selected on the basis of the results of a preliminary experiment on
female mice, in which groups of five mice were orally dosed with
7.5 mg/kg and 15 mg/kg, respectively, of methamidophos; in that
experiment the dose level of 7.5 mg/kg was tolerated with only mild
symptoms. Immediately after administration, each male was mated with
one untreated virgin female. After a 4-day mating period, this female
was removed and replaced by another female, and so on for 12 mating
periods, for a total of 48 days. After about 14 days from the mid-
period of each mating, the females were sacrificed and uteri removed
for examination. The total implants, viable implants, dead implants
(sum of the deciduomata, resorptions and the dead embryos and
foetuses) and the corpora lutea were counted. The treated males
exhibited no signs of toxicity. There was no compound-related
mortality. The fertility rate in the treated group was somewhat lower
than that in the control group in mating periods 2, 3 and 4. However,
as a similar low value was observed in the control group in mating
period 1, the findings were not considered to have been due to an
effect of the test compound. There were no statistically significant
differences between the control and treated groups with respect to
total implantations, viable implants, dead implants and pre-
implantation loss (estimated both directly as the difference between
corpora lutea and implantations and indirectly as implantations per
fertilized female).
Thus, the dominant lethal test on the male mouse does not provide
any relevant indication that methamidophos has a mutagenic activity at
the acute oral dose of 5 mg/kg bw (Herbold 1980a).
Rat - micronucleus test
Groups of rats (5 male and 5 female, NMRI/W77 strain/group) were
administered methamidophos (62.6% purity) twice by oral intubation at
doses of 0, 5 and 10 mg/kg bw. A positive control group received
twice 0.125 mg/kg bw of trenimon intraperitoneally. Delay time
between administrations was 24 hours. Six hours after the second
administration, animals were decapitated and bone-marrow smears were
prepared. The doses were selected after a preliminary test in which 5
animals received 2 × 5, 2 × 10 and 2 × 20 mg/kg of methamidophos, and
animals tolerated 2 × 10 mg/kg with slight symptoms. Poly-chromatic
erythrocytes, 1 000 per animal, were observed and the frequency of
such cells with micronuclei was calculated. Also the ratio of
polychromatic to normochromatic erythrocytes was determined. No
compound-related mortality occurred. Behaviour and motor activity were
not affected by the treatment. There were no significant differences
between negative control and methamidophos treated groups with respect
to the presence of micronucleated polychromatic erythrocytes. The
frequency of such cells was 2.6% in the negative control and 2.1% and
1.6% in 5 and 10 mg/kg groups, respectively. Activity of the positive
control was clearly observed in that a frequency of 53.7%
micronucleated polychromatic erythrocytes occurred in the trenimon-
treated group. There were no significant differences between control
and both trenimon and methamidophos treated groups, also with respect
to the ratio of polychromatic to normochromatic erythrocytes, i.e.
these compounds did not affect erythropoiesis. Thus, in the
micronucleus test on the rat, there was no indication of mutagenic
activity of methamidophos at doses up to and including 2 × 10 mg/kg
per os (Herbold 1981).
Salmonella/microsome test
Strains of Salmonella typhimurium (TA 1535, TA 1537, TA 100,
TA 98), with and without a metabolic activation system (S-9 mix
derived from the liver of Sprague-Dawley rats treated
intraperitoneally with Arochlor 1254) were tested at concentrations of
20, 100, 500, 2 500 and 12 500 µg/plate of methamidophos (62.6%
purity). Positive controls were cyclophosphamide (only for TA 1535 and
TA 100) and trypaflavin (only for TA 1537 and TA98). Negative controls
were dimethylsulphoxide (DMSO) for methamidophos and trypaflavin and
demineralized water for cyclophosphamide. Four plates per substance,
per dose, per strain were used. In all groups, two plates were used
for the total cell count. Results were considered positive when in at
least one strain a reproducible, dose-related increase of mutant cells
at least double that of the negative control occurred. Concentrations
higher than 500 µg/plate were slightly bacteriotoxic both with and
without S-9 mix, but were nevertheless useful for the evaluations of
the test. An increase of mutants greater than the double of the
respective negative controls, but not dose-related, was observed only
in two strains (TA 1535 and TA 1537) at 100 µg/plate without S-9 in
TA 1535, and at 100 µg/plate with S-9 and 100, 500, 2 500 µg/plate
without S-9 in TA1537. However, these results could not be reproduced
in a repetition experiment with TA 1535 and TA 1537. Positive controls
displayed the expected mutagenic effects.
Thus, under the conditions of the test, methamidophos showed no
mutagenic activity toward the tested strains of Salmonella typhimurium at doses up to and including 12 500 µg/plate, both with
and without S-9 Mix (Herbold 1980b).
Special Studies on Neurotoxicity
Groups of adult hens (9 to 18 months old) were given a single
dose of methamidophos (74% purity) by gastric intubation at levels of
0, 30 and 50.63 mg/kg body weight on days 0 and 21 simultaneously with
50 mg/kg of atropine sulphate intramuscularly. Eight hens for the
control and 10 and 12, respectively, for the treated groups were used.
Concurrently 500 mg/kg of tri-orthocresyl phosphate (TOCP) and
50 mg/kg of atropine sulphate were administered to 10 hens for a
positive control. In a separate portion of the study the acute oral
LD50 was found to be 29.75 mg/kg.
No delayed neurotoxic signs were observed in the control and
treated groups during a 42-day post-treatment observation period. The
dose level in the delayed neurotoxicity study were above the acute
oral LD50 and atropine was given as protection against acute death.
However some acute deaths did occur both at day 0 and 21. Acute signs
of toxicity did occur in most cases but disappeared by 24 hours. Hens
were sacrificed on day 42 or 43, and 7 hens from the control group,
9 from the TOCP group, 3 from the 33.75 mg/kg group or the LD50
study, 6 from the 30 mg/kg group and 4 from the 50.63 mg/kg group were
used for histopathological examination of the spinal cord and
peripheral nerves. No compound-related histopathological changes or
variations from normal were observed in the nervous tissues of the
examined hens. TOCP treated hens developed clinical signs of
neurotoxicity. Five had marked neuronal histological lesions, three
moderate and one slight (Kruckenberg et al 1979).
Special Studies on Antidotes
The lethality of methamidophos to rats (i.p. LD50, 15 mg/kg) is
similar to that of such potent organophosphate compounds as parathion
and paraoxon. Certain distinctive features of its chemical structure
and reported failure of cholinesterase inhibited with methamidophos to
reactivate spontaneously in insects prompted this study of its
reactions with mammalian cholinesterase to determine if the treatment
of poisoning requires modification. Atropine (10 mg/kg) or pradiloxime
(60 mg/kg) produced significant protection against lethality from
methamidophos (LD50 60 ± 0.4 and 52 ± 4.9 mg/kg, respectively).
Partial spontaneous recovery of inhibited cholinesterase activity was
observed. However, a single dose of pralidoxime, given simultaneously
with methamidophos, did not hasten the recovery of cholinesterase
activity (Robinson et al 1978).
Special Studies on Combined Toxicity
Methamidophos/mercaprophos
Acute oral LD50 values in male rats (Wistar albino) were
determined for methamidophos (62% purity), mercaprophos (88% purity)
separately administered, and for the equitoxic mixture of the two
compounds.
The comparison of the LD50 found for the equitoxic mixture with
the expected LD50 (assuming an additive effect) showed that
simultaneous oral administration of methamidophos and mercaprophos
resulted in only an additive acute toxic effect (Flucke 1978).
Methamidophos/parathion-ethyl
A similar study showed that simultaneous oral administration of
methamidophos (63.7% purity) and parathion-ethyl (97.8% purity)
resulted in only an additive acute toxic effect (Flucke and Kimmerle
1977).
Methamidophos/chlorpyrifos, cytrolane, cyolane
Equitoxic mixtures of methamidophos with either chlorpyrifos,
cytrolane or cyolane were acutely administered to male Wistar-II
albino rats to evaluate possible potentiation of acute toxic effects.
Comparison of the found and the expected LD50 (assuming an additive
effect) showed that simultaneous oral administration of each
combination resulted in only an additive or slightly under-additive
acute toxic effect between the two components (Thyssen 1977c).
Special Studies on Skin and Eye Irritation
A dermal irritation study using New Zealand white rabbits
indicated that 24 hours exposure to methamidophos (73.2% purity) was
not irritant for either abraded or non-abraded skin (Lamb et al
1980a).
Results of an eye irritation test using New Zealand white rabbits
indicated that methamidophos is a positive eye irritant. An
irreversible response was observed in one rabbit of the group, which
received an eye wash 45 seconds after the treatment (Lamb et al
1980a).
Special Studies on Feedingstuffs Palatability
Cattle were fed alfa alfa pellets treated with methamidophos at
levels of 0, 5 and 15 ppm (at or above the level expected in field-
treated plant material) for 4 weeks.
No significant differences in feed consumption or body weights
were observed between animals fed treated or untreated feed; the
animals initially showed some preference for treated feed, but by the
end of a week no preference was detected (Murphy et al 1976).
Acute Toxicity
Signs of toxicity were similar in mouse and rat and included
severe tremors, salivation, dyspnoea and, rarely, clonic convulsions.
These signs were evident within 5-10 minutes. Death occurred between
20-30 minutes and 72 hours. Animals surviving 72 hours showed complete
recovery within seven days. Autopsies done on animals dying shortly
after dosing showed pulmonary congestion and oedema and distension of
the stomach and intestines with gas (Cavalli and Hallesy 1968c).
The acute toxicity of methamidophos and of two impurities found
in technical methamidophos are summarized in Tables 1 and 2.
Short-Term Studies
Rabbit-dermal
Groups of rabbits (6 male and 6 female New Zealand/group) were
administered methamidophos (64.5% purity) dermally to either intact or
abraded skin with single daily applications corresponding to dose
levels of 0, 0.5, 5 mg/kg. The application was made 6 hours/day, 5
days/week for 3 weeks. The sample was applied as an aqueous emulsion.
Table 1. Acute Toxicity of Methamidophos
LD50
Species Sex Route Vehicle (mg/kg bw) References
Mouse F oral water 16.20 Cavalli et al 1968a
(95% pure)
Rat M oral deionized water 15.60 Cavalli and Hallesy 1968c
(95% pure)
F 13.00
Rat M oral dist. water 32.90 Thyssen 1977a
Rat M oral dist. water 21.60 Thyssen 1927b
Rat M oral Cremophor EL and 24.00 Thyssen 1977c
(63.7% pure) dist. water
Rat M oral Cremophor EL and 30.00 Flucke and Kimmerle 1977
(63.7% pure) dist. water
Rat M oral Cremophor EL and 28.95 Flucke 1978
(62% pure) dist. water
Rat M oral dist. water 18.00 Mihail 1981
(64.5% pure)
F 26.00
Rat M dermal 162.00 Heinmann 1981
24-h exp.
(64.5% pure)
F 108.00
Table 1. (con't)
LD50
Species Sex Route Vehicle (mg/kg bw) References
Rabbit M dermal undiluted 118.00 Cavalli and Hallesy 1968b
24-h exp.
(75% pure)
Rabbit M dermal undiluted 122.00 Lamb et al 1980b
24-h exp.
(73.2% pure)
F 69.00
Hen F oral not specified 29.75 Kruckenberg et al 1979
(74% pure)
Bobwhite M oral PEG-400 10.10 Nelson 1979b
quail F 11.00
Table 2. Acute Toxicity of Impurities of Technical Methamidophos
LD50
Compound Species Sex Route Vehicle (mg/kg bw) References
Dimethyl Ac. rat M Oral Prop.glycol: 694 Lamb and Anderson 1974a
(CH3O)2P(S) (SH) Ethanol 8:2
F Ethanol, 8:2 708
rabbit M&F Dermal undiluted &gt2 000 Lamb and Anderson 1974b
abraded
24-h exp.
Amidate rat M&F oral Prop. glycol: 410 Lamb and Anderson 1974a
(CH3O)2P(S)NH2 Ethanol, 8:2
rabbit M&F Dermal undiluted &gt2 000 Lamb and Anderson 1974b
abraded
24-h exp.
No mortalities occurred and all the animals were normal in
behaviour and appearance during the treatment period. No significant
differences were observed with respect to mean body weight in all
groups. Neither inflammation nor thickening of the treated skin was
seen. There were no noteworthy differences between control and treated
groups with respect to haematological, clinical-chemical and
urinalysis parameters. Marginal to distinct (19-35%) depression of
serum and erythrocyte cholinesterase activity occurred in the 5 mg/kg
groups. Brain cholinesterase was not significantly different between
control and treated groups. No treatment-related differences between
control and treated groups were seen in absolute and relative organ
weights or in gross and histopathological examinations. The no-effect
level for cholinesterase activity was 0.5 mg/kg bw/day, 5 mg/kg bw/day
being tolerated without apparent somatic effects (Heinmann and Nash
1981).
Observations in Humans
Thirteen reports on persons involved discontinuously in
activities related to synthesis, process development and pilot-plant
manufacture of methamidophos for 1 to 3 years, and 38 reports on
persons engaged in normal spraying operations (back-pack-, tractor-,
and helicopter-mounted equipment), including foliar, ground and
greenhouse applications of diluted emulsifiable formulations, did not
record any relevant complaints (Chevron Chemical Company 1968).
COMMENTS
Methamidophos was evaluated by the 1976 JMPR. An ADI was
allocated, based on a no-effect level observed in a 90-day dog study
which was not from IBT.
Some relevant toxicological studies supporting the 1976
Evaluation were carried out by IBT. Valid substitute studies have been
provided for some of the IBT studies.
No-effect levels for embryotoxic and teratogenic effects for
methamidophos were observed in the Himalayan rabbit.
Methamidophos was not mutagenic in the dominant lethal,
micronucleus and Ames tests.
A delayed neurotoxicity test was negative.
No valid long-term toxicity, reproduction or carcinogenicity
studies have been provided.
As no-effect levels could be determined in short-term studies
only, a temporary ADI was allocated.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Rat : 2 ppm in the diet equivalent to 0.1 mg/kg bw.
Dog : 1.5 ppm in the diet, equivalent to 0.04 mg/kg bw.
Estimate of Temporary Acceptable Daily Intake for Man
0 - 0.0004 mg/kg bw.
FURTHER WORK OR INFORMATION
Required (by 1985)
1. Long-term studies, or validation of the IBT long-term study on
rats.
2. A carcinogenicity study.
3. A reproduction study in mammals.
Desirable
Observations in humans.
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Herbold, B. SRA 5172 (methamidophos). Dominant lethal test on male
1980a mouse to evaluate SRA 5172 for mutagenic potential. Report
No. 9583 from Institut für toxicologie, Bayer, F.R.G.
submitted to the World Health Organization by Bayer, F.R.G.
(Unpublished)
1980b SRA 5172 (methamidophos). Salmonella/mikrosomen-test zur
Untersuchungen auf Punkt-Mutagene Wirkung. Report No. 9175
from Institut für toxicologie, Bayer, F.R.G. submitted to
the World Health Organization by Bayer, F.R.G. (Unpublished)
Herbold, B. SRA 5172 (methamidophos). Mikronucleus-test an der Maus
1981 zur Prüfung auf mutagene Wirkung. Report No. 9707 from
Institut für toxicologie, Bayer, F.R.G. submitted to the
World Health Organization by Bayer, F.R.G. (Unpublished)
Kao, T.S. and Fukuto, T.R. Metabolism of O,S-dimethyl-, propionyl- and
1977 hexanoylphosphoramidothioate in the housefly and white
mouse. Pest. Bioch. Physiol. 7:83-95.
Khasawinah, A.M.A., March, R.B. and Fukuto, T.R. Insecticidal
1978 properties, antiesterases activities and metabolism of
methamidophos. Pest. Bioch. Physiol. 9:211-281.
Kruckenberg, S.M., Fenwick, B.W., Brown, S.M., Kassenbaum, L.J. and
1979 Nilson, R.K. Acute delayed neurotoxicity study on monitor
technical. Study no. 79 ANHO1 from Department of Pathology,
Kansas State University, U.S.A., prepared for Mobay Chemical
Corporation, U.S.A., submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)
Lamb, D.W. and Anderson, R.H. The acute oral toxicity of dimethyl
1974a acid and amidate. Report No. 73123 from Chemagro
Agricultural Division, Mobay Chemical Corporation, Kansas,
submitted to the World Health Organization by Bayer,
F.R.G.(Unpublished)
1974b The acute dermal toxicity of dimethyl acid and amidate.
Report No. 73123 from Chemagro Agricultural Division, Mobay
Chemical Corporation, Kansas, submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)
Lamb, D.W., Hixson, E.J. and English, T.D. Eye and dermal irritation
1980a of methamidophos. Report No. 121 (study nos. 80-023-06 and
80-033-10) from Corporate Toxicology Department, Mobay
Chemical Corporation, Kansas, submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)
Lamb, D.W., Hixwon, E.J. and Delphia, K.L. Acute dermal toxicity of
1980b methamidophos (monitor) to rabbits. Report no. 80-002-02
from Corporate Toxicology Department, Mobay Chemical
Corporation, Kansas, submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)
Lamb, D.W., Roney, D.J. and Schroeder, R.S. Accumulation and
1980c persistence of residues in bluegill exposed to
methamidophos-14C (Monitor). Report no. 80-611-01 from
Corporate Toxicology Department, Mobay Chemical Corporation,
Kansas, submitted to the World Health Organization by Bayer,
F.R.G. (Unpublished)
Machemer, L. SRA 5172 (methamidophos). Studies of embryotoxic and
1979 teratogenic effects on rabbits following oral
administration. Report no. 8410 from Institut für
toxicologie, Bayer, F.R.G., submitted to the World Health
Organization by Bayer F.R.G. (Unpublished)
Mihail, F. SRA 5172 (tamaron Wrst.). Bestimmung der akuten toxizität
1981 (LD50). Report from Institut für Toxicologie, Bayer,
submitted to the World Health Organization by Bayer, F.R.G.
(Unpublished)
Murphy, J.J., McNamara, F.T., Lamb, D.W. Cattle acceptance
1976 (palatability) of alfa alfa pellets treated with monitor.
Report no. 41127 from Chemagro Agricultural Division, Mobay
Chemical Corporation, Kansas, submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)
Nelson, D.L. Acute oral toxicity of monitor technical to bobwhite
1979b quail. Report No. 67933 from Corporate Toxicology
Department, Mobay Chemical Corporation, Kansas, submitted to
the World Health Organization by Bayer, F.R.G, (Unpublished)
Robinson, C.P., Beiergrohslein, D., Smith, P.W. and Crane, C.R.
1978 Reaction of methamidophos with mammalian cholinesterases. US
NTIS AD Rep. AD-058, 683: 7; 443 (Abstract No. 79-1717).
Thyssen, J. SRA 5172 (tamaron-Wrst.). Bestimmung der akuten toxizität
1977a (LD50). Report from Institut für Toxicologie, Bayer,
F.R.G., submitted to the World Health Organization by Bayer,
F.R.G. (Unpublished)
1977b SRA 5172 (Tamaron-Wrst.). Bestimmung der akuten toxizität
(LD50). Report from Institut für Toxicologie, Bayer,
submitted to the World Health Organization by Bayer, F.R.G.
(Unpublished)
1977c Untersuchungen zur Kombinations-Toxizität von chlorpyrifos,
cytrolane, cyolane, tamaron, gusathion-äthyl and gusathion-
methyl-wirkstoff. Report No. 7179 from Institut für
toxicologie, Bayer, submitted to the World Health
Organization by Bayer, F.R.G. (Unpublished)